Dysregulated cellular function underlies many pathological conditions. Identification of molecular effectors of proper cell function along with methods of preventing or reversing cell dysfunction are required for promoting or maintaining proper or enhanced cellular function. Dysregulated gene expression is implicated in a variety of diseases such as cancer, diabetes, obesity, cardiovascular diseases and neurodegeneration. Discerning which molecular targets are most directly associated with a disease or condition is paramount to treating or preventing the disease and condition.
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play integral roles in immune regulation. Expressed on activated T cells, PD-1 is activated by PD-L1 and PD-L2 expressed by stromal cells, tumor cells, or both, initiating T-cell death and localized immune suppression, potentially providing an immune-tolerant environment for tumor development and growth. Conversely, inhibition of this interaction can enhance local T-cell responses and mediate antitumor activity in nonclinical animal models. In the clinical setting, treatment with antibodies that block the PD-1-PD-L1 interaction have been reported to produce objective response rates of 7% to 38% in patients with advanced or metastatic solid tumors, with tolerable safety profiles.
The programmed death 1 (PD-1) receptor and programmed death-ligand 1 (PD-L1) play integral roles in immune regulation. PD-L1 (also called B7-H1 or CD274) is a 290 amino acid protein receptor ligand encoded by the CD274 gene and is expressed widely on both lymphoid and non-lymphoid tissues such as CD4 and CD8 T-cells, macrophage lineage cells, peripheral tissues as well as on tumor cells, and virally-infected cells (Dong et al. 1999, Nature Med.). PD-L1 binds to receptors PD-1 and B7-1 which belong to the CD28/CTLA-4 (cytotoxic T lymphocyte antigen)/ICOS (inducible co-stimulator) family of T-cell co-inhibitory receptors and attenuates the immune response by inhibiting T-cell activation. PD-L1 binding to PD-1 or B7-1 results in decreased T-cell proliferation and cytokine secretion, compromising humoral and cellular immune responses in diseases such as cancer, and viral infection.
The expression of PD-L1 on tumor cells and virally-infected cells is exploited by tumors and chronic viral infections to evade immune response. PD-L1 is expressed on a wide variety of tumors and studies on animal models have shown that PD-L1 on tumors inhibits T-cell activation and lysis of tumor cells and may lead to increased death of tumor-specific T-cells. In chronic viral infections, PD-L1 expressed on virally-infected cells binds to PD-1 on virus-specific T-cells and these T-cells become “exhausted” with loss of effector functions and proliferative capacity. The PD-1-PD-L1 system also plays an important role in induced T-regulatory cell development and in sustaining T regulatory cell function. Accordingly, as PD-L1 plays an important role in tumor immunity and infectious immunity, a composition that decreases expression of a CD274 gene or a PD-L1 protein is an ideal target for immunotherapy.
However, cardiac side effects have been observed in treatments that result in the decrease of PD-L1 expression. For example, in one study, targeted inhibition of PD-L1 with pembrolizumab was associated with acute heart failure due to autoimmune myocarditis (Laubli et al., Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma, Journal for ImmunoTherapy of Cancer (2015) 3:11).
PD-1 is an immunosuppressive receptor belonging to an immunoglobulin family and is encoded by the PDCD1 gene. PD-1 is a molecule having a function of suppressing the immune activation signals of T-cells activated by stimulation through an antigen receptor. For example, analysis of PD-1 knock-out mice demonstrates that PD-1 signals play important roles in suppression of autoimmune diseases such as autoimmune dilated cardiomyopathy, lupus-like syndrome, autoimmune encephalomyelitis, systemic lupus erythematosus, graft-versus-host disease, type I diabetes mellitus, and rheumatoid arthritis. Accordingly, as PD-1 plays an important role in autoimmune diseases, a composition that enhances expression of a PDCD1 gene or a PD-1 protein is an ideal target for immunotherapy.
As such, there exists a need for compositions and methods of decreasing expression of a CD274 gene or a PD-L1 protein while increasing expression of a PDCD1 gene or a PD-1 protein in a subject.